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Proof of the elastotic concept was supplied by a recent milestone study showing that two common single nucleotide polymorphisms in the coding region of the lysyl oxidase-like 1 (LOXL1) gene located on chromosome 15 were specifically associated with XFS and XFG in two Scandinavian populations accounting for virtually all XFS cases (Thorliefsson et al., 2007). These findings have been substantiated in other populations (Fingert et al., 2007; Hewitt et al., 2007; Hayashi et al., 2008; Aragon-Martin et al., 2008).

LOXL1 is a member of the lysyl oxidase family of enzymes, which are essential for the formation, stabilization, maintenance, and remodeling of elastic fibers and prevent age-related loss of elasticity of tissues (Oleggini et al., 2007). Lysyl oxidase serves both as a cross-linking enzyme and a scaffolding element which ensures spatially defined deposition of elastin (Liu et al., 2004). It also regulates the promoter of elastin (Oleggini et al., 2007). Genetic variation in LOXL1 has been suggested to be a factor in spontaneous cervical artery dissection, a common cause of stroke in relatively young patients (Kuhlenbaumer et al., 2007). Overactivity of lysyl oxidase, with localization of the enzyme in blood vessel walls and in plaque-like structures, has been found in Alzheimer’s disease (Gilad et al., 2005). LOXL1 protein is a major component of exfoliation deposits and appears to play a role in its accumulation and in concomitant elastotic processes in intra and extraocular tissues of XFS patients.

A number of nongenetic factors, including dietary factors, autoimmunity, infectious agents, and trauma, have also been hypothesized to be involved in the pathogenesis of XFS. Altogether, it appears that XFS represents a complex, multifactorial, late-onset disease, involving both genetic and nongenetic factors in its pathogenesis.

Mechanisms of glaucoma development

Friction between the iris and the XFM covering the lens surface leads to disruption of the iris pigment epithelium at the sphincter and pigment liberation. Just as the iris scrapes XFM from the lens surface, the material on the lens causes

rupture of iris pigment epithelial cells at the ruff and sphincter region with concomitant dispersion of pigment into the anterior chamber. Blockage of aqueous outflow by a combination of pigment and XFM deposited in the intertrabecular spaces, and XFM in the juxtacanalicular meshwork, and beneath the endothelium of Schlemm’s canal is believed to be the major cause of elevated IOP.

Although XFG is characteristically a highpressure disease, pressure-independent risk factors, such as an impaired ocular and retrobulbar perfusion and abnormalities of elastic tissue of the lamina cribrosa, may be present and further increase the individual risk for glaucomatous damage. In a prospective study, Puska et al. (1999) found that in normotensive XFS patients with clinically unilateral involvement, in whom IOP was equal throughout the follow-up period, disc changes took place only in the involved eye, suggesting that the exfoliation process itself may be a risk factor for optic disc changes.

Management

Medical therapy

Initial medical treatment of XFG generally consists of topical prostaglandin analogs and aqueous suppressants. In one crossover trial, bimatoprost provided a statistically greater IOP reduction for all time points and for the mean diurnal curve after 3 months of therapy (35% reduction with bimatoprost vs. 31% reduction for latanoprost; Konstas et al., 2007a, b). Another 24-h study showed that both latanoprost and travoprost reduced IOP at each time point and for the 24-h curve from untreated baseline (Konstas et al., 2007a, b). However, travoprost provided a slightly greater hypotensive effect for the 24-h curve (mean difference between groups was 0.5 mmHg). Konstas et al. (2004) demonstrated the benefit of IOP reduction and suggested a target IOP of r17 mmHg and lower to prevent or slow progressive damage. Latanoprost provided a narrower range of diurnal IOP fluctuation compared to timolol. In addition to lowering IOP, prostaglandin analogs may interfere with the disease

process. Latanoprost treatment had a marked effect on the aqueous concentration of TGF-b1, MMP-2, and TIMP-2 in XFG patients (Konstas et al., 2006a, b).

Aqueous suppressants do not interfere with the mechanism of the cause of progression of trabecular damage, i.e. iridolenticular friction and disruption of the iris pigment epithelial cells. Cholinergic agents have multiple beneficial actions in eyes with XFS. Not only do they lower IOP, but by increasing aqueous outflow, they should enable the trabecular meshwork to clear more rapidly, and by limiting pupillary movement, should slow the progression of the disease. Aqueous suppressants, on the other hand, by decreasing aqueous secretion, result in decreased aqueous flow through the trabecular meshwork. Becker, 1995 has presented suggestive evidence that treatment with aqueous suppressants leads to worsening of trabecular function.

Pilocarpine has multiple beneficial actions in eyes with XFS. Not only does it lower IOP, but by increasing aqueous outflow, it should enable the trabecular meshwork to clear more rapidly, and by limiting pupillary movement, should slow the progression of the disease. Theoretically, miotics should be the first line of treatment. The use of miotics, unfortunately, has almost disappeared from use in glaucoma on the basis that they are considered a q.i.d. drug and because many patients have nuclear sclerosis and miotics may reduce visual acuity or dim vision sufficiently to create difficulty. Pilocarpine has also been shown to blunt an early morning IOP spike which often occurs in the supine position after a night’s sleep (Barkana et al., 2006). The long-term use of miotics may lead to the development of posterior synechiae in patients with XFS. However, we have found that 2% pilocarpine q.h.s. can provide sufficient limitation of pupillary mobility without causing these side effects. An international, multiinstitutional prospective trial (International Collaborative Exfoliation Syndrome Treatment Study) comparing latanoprost and 2% pilocarpine q.h.s versus timolol/Cosopt for patients with XFS and ocular hypertension or glaucoma has been completed and analysis is in progress.

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Laser surgery

Argon laser trabeculoplasty (ALT) is particularly effective in eyes with XFS. The baseline IOP is usually higher in XFG than in eyes with POAG undergoing ALT and thus the initial drop in IOP is greater in XFG. Primary ALT can delay the use of medical therapy for up to 8 years in a significant proportion of these patients (Odberg and Sandvik, 1999). There is a gradual reduction in success over time, with long-term rates dropping to approximately 35–55% at 3–6 years.

Approximately 20% of patients develop sudden, late rises of IOP within the first 2 years after treatment (Ritch and Podos, 1983). Continued pigment liberation may overwhelm the restored functional capacity of the trabecular meshwork, and maintenance miotic therapy to minimize papillary movement after ALT might counteract this. We have found empirically that 2% pilocarpine q.h.s. is sufficient to provide this protection.

Selective laser trabeculoplasty (SLT) needs to be further evaluated as an effective and safe alternative to ALT in the treatment of XFG. In a prospective trial, Gracner (2002) found that the success rate after 12 months (Kaplan–Meier survival analysis) was 97%, after 24 months 88%, after 36 months 76%, and after 48 months 71%. Further studies are necessary. It should be noted that SLT in eyes with heavily pigmented trabecular meshworks may cause marked IOP elevations, even necessitating filtration surgery (Harasymowicz et al., 2005).

Operative surgery

The results of trabeculectomy are comparable to those in POAG. In a recent study, trabeculectomy with MMC obtained better 24-h IOP control than successful maximal medical therapy in patients with advanced XFG or POAG (Konstas et al., 2006a, b). However, surgical complications are more common in patients with XFG. In some cases high preoperative IOP may predispose to choroidal hemorrhage, or effusion. Weakened zonular support may allow intraoperative lens movement, or even in extreme cases subluxation.